CETP inhibitors, as a class, are characterized by high binding activity. Such CETP inhibitors are generally hydrophobic, however, with the consequence that they have extremely low aqueous solubility and have low oral bioavailability. Such compounds have generally proven to be difficult to formulate for oral administration such that high bioavailabilities are achieved.
Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of death in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.
Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid-associated contributor to CHD. Low HDL-cholesterol is also a known risk factor for CHD (Gordon, D. J., et al.,: “High-density Lipoprotein Cholesterol and Cardiovascular Disease”, Circulation, (1989), 79: 8-15).
High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated, with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.
Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.
No wholly satisfactory HDL-elevating therapies exist. Niacin can significantly increase HDL, but has serious toleration issues that reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-cholesterol only modestly (˜10-12%). As a result, there is a significant unmet medical need for a well-tolerated agent that can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.
CETP inhibitors have been developed that inhibit CETP activity, and thus, if present in the blood, should result in higher HDL cholesterol levels and lower LDL cholesterol levels. To be effective, such CETP inhibitors must be absorbed into the blood. Oral dosing of CETP inhibitors is preferred because to be effective such CETP inhibitors must be taken on a regular basis, such as daily. Accordingly, it is preferred that patients be able to take CETP inhibitors by oral dosing rather than by injection.
However, it has proven to be difficult to formulate CETP inhibitors for oral administration such that therapeutic blood levels are achieved. CETP inhibitors, in general, possess a number of characteristics that render them poorly bioavailable when dosed orally in a conventional manner. CETP inhibitors tend to be quite hydrophobic and extremely water insoluble, with solubility in aqueous solution of usually less than about 10 μg/ml and typically less than 1 μg/ml. Often the aqueous solubility of CETP inhibitors is less than 0.1 μg/ml. Indeed, the solubility of some CETP inhibitors is so low that it is in fact difficult to measure. Accordingly, when CETP inhibitors are dosed orally, concentrations of CETP inhibitor in the aqueous environment of the gastrointestinal tract tend to be extremely low, resulting in poor absorption from the GI tract to blood. The hydrophobicity of CETP inhibitors not only leads to low equilibrium aqueous solubility but also tends to make the drugs poorly wetting and slow to dissolve, further reducing their tendency to dissolve and be absorbed from the gastrointestinal tract. This combination of characteristics has resulted in the bioavailability for orally dosed conventional crystalline or amorphous forms of CETP inhibitors generally to be quite low, often having absolute bioavailabilities of less than 1%.
Various attempts have been made to improve the aqueous concentration of CETP inhibitors, but generally have met with limited success. Conventional methods of formulation do not provide sufficient solubilities and thus poor oral bioavailabilities have been obtained. Pre-dissolving CETP inhibitors in hydrophilic solvents such as acetone or PEG followed by delivery as a solution have failed due to inadequate solubility in the solvent or precipitation upon dilution into the aqueous medium. Suspensions of crystalline drug do not provide sufficient concentrations of drug in solution due to very low aqueous solubilities and therefore yield inadequate blood levels.
One approach that has been disclosed to formulate CETP inhibitors is the formation of CETP solutions in lipids. Solutions in medium chain triglycerides have been of value either as oral solutions or encapsulated in softgels. However, the solubility (65 mg/mL or less) for some of the most potent and useful CETP inhibitors known to the inventors has limited the dose to 30 mg in a reasonable sized softgel. The efficacious dose is expected to be several multiples of this and therefore may require administration of more than 2 softgels per day.
It has also been found that it is necessary to administer triglyceride solutions with food in order to achieve efficacious blood levels of CETP inhibitors. Food effects of 20-30× have been observed in man for some CETP inhibitors, with considerable variability between patients. The food effect is the ratio of plasma AUC values measured for administration of drug with a meal vs. administration in the fasted state. In addition, there is minimal CETP inhibition in the absence of food due to low fasted plasma exposure. As a result, labeling would need to indicate administration with food. This strong dependence of exposure on food could compromise the effectiveness of this medication in the treatment of atherosclerosis if there is a lack of compliance with labeling instructions.
Therefore, there remains a need to develop oral formulations of CETP inhibitors that would reduce the food effect substantially, primarily by improving fasted exposure, thereby minimizing patient-to-patient variability in clinical outcome. An increase in the dose per capsule would also be a desirable improvement.
Lack of mixing between oil formulations and the aqueous environment of the GI tract is known to lead to variable gastric emptying and thus variable absorption. A frequent means of increasing fasted bioavailability of hydrophobic drugs is to use a surfactant or combination of surfactants to produce an emulsion, which, if of sufficiently small particle size can lead to enhanced absorption of the drug. Lipid solutions containing surfactants that spontaneously form emulsions when mixed with an aqueous medium are referred to in the literature as self-emulsifying drug delivery systems (SEDDS) (S. Charman, et. al., Pharm Res., vol. 9, 87 (1992)). They are isotropic mixtures of oil, typically medium chain triglycerides, and non-ionic emulsifier that yield fine emulsions when gently mixed with aqueous fluid, such as in the stomach and intestine, and have the appropriate polarity for fast drug release (C. W. Pouton, Adv. Drug Deliv. Rev, vol. 25, 47 (1997); P. P. Constantinides, Pharm. Res., vol. 12, 1561 (1995); A. Humberstone and W. Charman, Adv. Drug Del. Rev., vol 25, 103 (1997)). Early SEDDS were defined as forming an emulsion with particle size below 5 microns (S. Charman, et. al., Pharm Res., vol. 9, 87 (1992)) and utilized MIGLYOL® and a single surfactant, Tagat TO, which has an HLB (hydrophilic-lipophilic balance) of 10, to form a emulsion with a droplet size of 3 microns. Tagat is not available for human use as are other excipients with the appropriate properties.
Much of the effort in both the open and patent literature has been invested in formulations of cyclosporin. A formulation of cyclosporin that was found to increase bioavailability by in situ generation of an emulsion utilized long chain triglyceride, a polyglycolyzed glyceride, and ethanol and was marketed as Sandimmune® (Cavanak (Sandoz)). See U.S. Pat. No. 4,388,307 (1983). This had the disadvantage of considerable variability in oral bioavailability and PK profile. Subsequently, a self-microemulsifying system was developed (Meinzer, (Sandoz) WO 93/20833; Ritschel, Clin. Transplant., vol. 10, 364 (1996)) using polyethoxylated hydrogenated castor oil (Cremophor® RH40), corn oil mono-, di- and triglycerides, propylene glycol and ethanol. This softgel formulation, marketed as Neoral®, reduced variability in exposure and also reduced the moderate food effect (Mueller, Pharm . Res. vol 11, 151 (1994)).
Lipophilic solvents have been used in place of ethanol or propylene glycol which will not migrate to the shell and affect shell integrity and/or volatilize and thus impact on the concentration in the fill and on solubility. Triacetin has been used as a lipophilic cosolvent for cyclosporin microemulsion preconcentrates with a long chain triglyceride and high HLB surfactant (Hong (Chong Kun Dang Corp.) WO 99/000002). It has also been used alone and in a mixture with propylene glycol dicaprylate/dicaprate and a high HLB surfactant for ketoprofen and related anti-inflammatory acids (Shelley and Wei (Scherer) WO 95/31979A).
U.S. Pat. No. 5,993,858 discloses the use of an oil, high HLB surfactant, cosurfactant and triacetin as cosolvent for self-emulsifying formulations of hydrophobic drugs. Propylene carbonate has also been used as a lipophilic solvent for cyclosporin self-emulsifying systems (Woo (Novartis) WO 97/48410 and U.S. Pat. No. 5,958,876 (1999)). Use of ethyl lactate as a cosolvent for cyclosporin formulations, including clinical evaluation, has also been reported (WO 00/40219).